Discovery of Polymyxin-based Antibacterial Agents Active Against Multi-Drug Resis

描述（由申请人提供）：多重耐药病原菌的出现对人类生命和国家卫生保健系统构成了严重且日益严重的威胁。这些“超级细菌”现在每年导致10万人死亡，估计在美国增加了200亿美元的医疗成本。特别是，肺炎克雷伯菌、大肠杆菌、鲍曼不动杆菌和铜绿假单胞菌等革兰氏阴性菌株的扩大和NDM-1表型的迅速传播令人严重关切。对于许多革兰氏阴性感染，粘菌素（多粘菌素E）仍然是“最后手段”的唯一选择，因为碳青霉烯类不再具有活性，并且已经报告了替加环素耐药病例。目标和目标：我们的目标是生产基于粘菌素的新型抗生素，这种抗生素对耐药的“超级细菌”有活性，并且比目前的“最后防线”抗生素具有更好的安全性。这项研究将提供针对耐药致病菌的新型候选药物，也将提供对抗生素引起的肾毒性（肾毒性）的起源和机制的详细科学理解。我们将详细了解粘菌素是如何杀死细菌的。从长远来看，为肾毒性分析而开发的检测方法将在药物研究的所有领域被证明是有价值的，从而为抗生素-肾脏和更一般的药物-肾脏毒性筛查提供工具。新的粘菌素衍生物将对严重的革兰氏阴性超级超级细菌具有活性，并且可以攻击细菌的药物敏感和耐药菌株。途径和方法：该项目将使用世界上第一个快速合成1400个粘菌素类似物的合成方法，对结构-活性和结构-毒性关系进行前所未有的系统研究。这些新化合物将对耐药革兰氏阴性菌，特别是NDM-1菌株的活性进行优化，然后对其作用方式、稳定性、细胞毒性和肾毒性进行评估。它们还将被描述为与细菌膜和分子靶标（脂质A）的结合。这将导致药物作用的体内原理证明和药代动力学研究，为将来的临床前评估选择化合物。

DESCRIPTION (provided by applicant): The emergence of multi-drug resistant pathogenic bacteria represents a serious and growing threat to human lives and national healthcare systems. These 'supebugs' now kill 100,000's of people each year and are estimated to add $20bn in healthcare costs in the US. In particular, the expansion of Gram-negative strains such as Klebsiella pneumonia, Escherichia coli, Acinetobacter baumannii and Pseudomonas aeruginosa and the rapidly spreading NDM-1 phenotypes are of grave concern. For many of these Gram-negative infections, colistin (polymyxin E) remains the only option of 'last resort', where the carbapenems are no longer active, and cases of tigecycline resistance have been reported. Aims & Objectives: We aim to produce new antibiotics, based on colistin, that are active against resistant 'super-bugs' and that have better safety profiles than current 'last-resor' antibiotics. The research will deliver novel drug-candidates targeted at resistant pathogenic bacteria, and will also provide a detailed scientific understanding of the origins and mechanisms of antibiotic-induced kidney toxicity (nephrotoxicity).We will develop a detailed understanding of how colistin works to kill bacteria. In the longer term, the assays developed for profiling of nephrotoxicity will prove valuable in all areas of drug research, thus providing tools for both antibiotic-renal and more general drug-renal toxicity screening. The new colistin derivatives will be active against the serious Gram-negative super superbugs and attack both drug-sensitive and drug-resistant strains of the bacteria. Approach & methods: This program will use a world first synthetic method for the rapid synthesis of 1,400 colistin analogs for an unprecedented systematic investigation of structure-activity and structure- toxicity relationships. These novel compounds will be optimized for activity against drug-resistant Gram-negative bacteria, in particular NDM-1 strains, and then evaluated for mode of action, stability, cell toxicity and nephrotoxicity. They will also be profiled for binding to the bacterial membranes and molecular target (Lipid A). This will lead to in vivo proof-of-principle for drug action and pharmacokinetic studies for the selection of compounds for future pre-clinical evaluation.